In the other hand, MSCs act also as immunomodulators, by reducing inflammatory activity and were used as a racehorse cure with no immunoreaction, for the bone repair of rats, in a human trial for Crohn’s disease, and for perianal fistula, as outlined in a review publication. The absence or low immunogenicity of MSCs will allow their mass production, a better characterization, and the decrease of cost. This positive characteristic can be used for gene and cell therapy preclinical tests on animals before translational application, by using the MSCs that are planned to be utilized in the clinical trials (e.g., culture media, approved cells for clinical used by Federal Agencies). Human MSCs (hMSCs) were injected in different animals without any adverse events reported: mouse, rat, rabbit, zebrafish, swine, and dog, and as review for xenotransplantation of hMSCs. For the past 20 years, human MSCs were used in animal studies, with successes, on the basis of the low probabilities that the xenotrans-plantation of human cells in animals will trigger an inflammatory response and the human MSC rejection. In vitro studies showed that human bone marrow stem cells (BMSCs) are not recognized by T-lymphocytes but can suppress the proliferation of the T-lymphocyte. Functional MSCs do not express or express a very low level of HLA-DR (major histocompatibility complex class II, MHC II), meaning that MSCs have a lower immunogenicity than that of other cells. The activation of the HLA Class II leads to a rejection of transplanted cells or organs. In addition to this, the absence of HLA class II protein is a key factor, because MSCs could be used for allogeneic graft on patients, facilitating the use of MSCs in cell therapies. (b) MSCs have anti-inflammatory potential and immune-modulatory properties, and promote cell growth and tissue repair, through the secretion of cytokines and extracellular vesicles. published a list of the minimal criteria defining the MSC: MSC must express CD73, CD90, and CD105, and must lack the expression of CD14, CD19, CD34, CD45, and HLA-DR in addition, MSCs must differentiate into cells originated from the three embryonic stem cell germ layers (endoderm, ectoderm, and mesoderm ) such as adipocytes, chondrocytes, and osteoblasts, as the most used. Even with a self-renewal capacity, the aging of the MSC could be a major problem with an increase of mutation and loss of differentiation capacity. (a) They can differentiate into different types of cells (before or after transplantation), and the self-renewal property of the MSC is very important, but it is a critical characteristic that must be understood. MSCs curative properties and advantages can be divided in three different parts: However, there is always a risk that MSCs could transform into sarcoma, requiring a long-term follow-up on preclinical animal studies and clinical trials, up to 15 years based on the Food and Drug Administration guidelines (FDA). They can be cultured easily, and their stemness is characterized by the capacity of the MSC to self-renew and maintain the stemness properties, being passaged many times without karyotype alteration. They adhere quickly to the cell culture surface, and their morphology is fibroblastic. In the organism, the function of the MSC is to support the structure of the organs but also to generate cells of the specific organ when it is required. MSCs are pluripotent stem cells that were discovered around 30 years ago, and they can be isolated from bone marrow, adipose tissue, Wharton’s jelly, periosteum, villous chorion, fetus, and dental pulp, and there are no ethical issues. MSCs are very popular cells used in the research and over sixty-eight thousand publications involving the use of MSCs were published on PubMed, as of January 2021. This review is not focused on presenting the different types of stem cells used for cell and gene therapies, but it is focused on the MSCs and cell sheet engineering with MSCs. The European Medical Agency approved cell therapies in the past few years: Chondrocelect was the first approved cell therapy in 2009. The iPSCs can be engineered by the transfection of four different factors into somatic cells, but as for the ESCs, the iPSCs have also raised ethical issues, and clinical trials are conducted all over the world, but mainly in the USA, China, Japan, and France. Ethical debates about the use of ESCs make their use more difficult for human application, even if clinical trials have been conducted recently with ESCs. Different types of stem cells are used for research and for translational medicine: embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs).
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